Derivatives of 3-aza-bicyclo (3: 2: 0) heptane-2, 4-dione



United States Patent DERIVATIVES 0F 3AZABICYCLO (322:0) HEPTANE-2,4-DIONE Charles H. Grogan, Falls Church, Va., and Leonard M. Rice, Baltimore, Md., assignors to The Geschlckter Fund for Medical Research, Inc., Washington, D. C., a corporation of New York No Drawing. Application October 10, 1955, Serial No. 539,653

11 Claims. (Cl. 260-2475) This invention relates to compositions of matter, particularly to chemo-therapeutic organic compounds that are also of value as synthetic and pharmaceutical intermediates in preparing other chemo-therapeutic agents. More particularly the invention relates to compounds possessing bronchiodilatory, antispasmodic and local anesthetic properties in varying degrees.

Specifically this invention relates to dialkylaminoalkyl imides of l,2-cis-cyclobutane dicarboxylic anhydride, their simple and quaternary salts.

It is a basic object of the present invention to provide novel organic compounds and methods for the prepara tion thereof.

It is another object of the invention to provide novel, physiologically active compounds characterized by chemotherapeutic or medicinal properties, particularly bronchiodilatory, antispasmodic and local anesthetic activity.

These and other objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and certain specific examples of particular members thereof as well as general and specific methods of their preparation.

Generally stated, the novel compounds discovered are obtained by reacting the appropriate dialkylaminoalkylamine with the anhydride of 1,2-cis-cyclobutane dicarboxylic acid to form the intermediate amic acid which is cyclized to the imide by heating for 2 hours at 170 180 C. The imides are isolated directly from the re action mixture by vacuum distillation and are then converted to simple or quaternary salts by reaction with an acid or an alkyl halide respectively in suitable media.

0 n H H nc-co I (L N (CH2)..N=R ncc 11 HA 8 J Formulal Formula 2 The simple salts of these imides, formed on the side chain nitrogen are illustrated by Formula 2, and the Patented Aug. 6, 1957 monoquaternary salts, likewise formed on the side chain nitrogen are illustrated by Formula 3.

A- on =R i) X- Formula 3 In these formulae A represents the azabicycloheptanedione nucleus, n a number from 1 to 6, R represents 2 alkyl groups with from 1 to 6 carbon atoms, and R an alkyl group with from 1 to 6 carbon atoms or an alkylene group containing 3 carbon atoms. The structure (N=R) may represent a heterocyclic ring namely, morpholine, piperidine, pyrrolidine, piperazine or N- methyl piperazine. X represents an anion, namely, chloride, iodide, bromide, acetate or sulfate. In the quaternary salts R may be the same as or different from R in any of the formulae given.

The following examples of specific compounds and methods of their preparation will illustrate the manner in which they are obtained by the application of the general synthesizing procedure to particular members of the class of compounds discovered. It will be understood, however, that the following examples are merely illustrative and are not, nor are they intended to be, exhaustive of all the compounds embraced by this invention.

EXAMPLE I N dimethylaminoeihyl 3 azabicyclo(3:2:0)heptane- 2,4-dlone simple salts and quaternary salts The inside-0.2 mole of 1,2-cis-cyclobutane dicarboxylic anhydride was weighed into a 50 ml. 24/40 flask and 0.2 mole of dimethylaminoethylamine added rapidly in one lot. An exothermic reaction took place and the mass soon liquified. It was stirred until homogeneous (or heated if necessary to obtain a homogeneous liquid phase) and reweighed. Any amine lost (usually none) was replaced and a 12% excess of amine added. The reaction mixture was stirred until again homogeneous and heated slowly to l70-180 C. It was maintained at this temperature until water was no longer evolved (usually 2 hours) to cyclize the amic acid initially formed to the imide. Following the heating period, the flask was connected directly to a vacuum distillation apparatus and heated slowly to the boiling point so as to remove any lower boiling material such as unreacted amine. The material was distilled and the whole distilled between 1l4-116 C./l mm. It was redistilled and there was obtained 26.5 grams of imide, B. P. 86- 94 C./0.08 mm. as a clear, colorless, oily liquid, n =l.4938.

Carbon, H drogen, Nitrogen,

Percent ercent Percent Calculated 61. 20 8. 22 14. 28 Found E1. 32 8. 24 32 absolute ethanol increased the melting point to 259- 260 C.

Ionic iodide: Calculated-37.53%; found37.31%.

EXAMPLE II N diethylaminoethyl 3 azabicyclo(3:2:0)heptane- 2,4-dine simple and quaternary salts The imide.This imide was prepared ,in a manner analogous to that detailed under Example I by the re action of 0.2 mole of diethylaminoethylamine with 0.2 mole of the anhydride. On vacuum distillation 29 grams of a colorless oily liquid, B. P. 93-100" C./0.2 mm. was obtained, n =1.491O.

Nitrogen, Percent Carbon Percent Hydrogen, Percent N-dimethylaminopropyl-3-azabicyclo(3:2:0)heptane- 2,4-di0ne simple and quaternary salts The imide.--Reaction of 0.2 mole of dimethylamino- Calculated 8. Found 8.

pylamine with 0.1 mole of the anhydride as detailed under Example I yielded 16.6 grams of the title imide, B. P. 103 C./O.l mm., n "=1.49l8.

Carbon, Hydrogen, Nitrogen,

Percent Percent Percent Calculated E5. 51 9. 31 11. 76 Found 65. 63 9. 21 12.01

The monohydrochl0ride.-This was formed from the imide in isopropanol with an excess of alcoholic HCl and precipitation with ether, M. P. 149-151 C. not changed on recrystallization.

Ionic chloride: Calculated-l2.90%; found-13.l0%.

The m0n0methiodide.-This was formed from the imide in acetone with a slight excess of methyl iodide, M. P. 184-185 C. not changed on recrystallization.

Ionic iodide: Calculated-33.37%; found33.43%.

EXAMPLE V N-morpholinopropyl-3-azabicyclo(3:2.'0)heptane- 2,4-di0ne simple and quaternary salts The imide.This was formed by reaction of 0.1 mole of morpholinopropylamine with 0.1 mole of the anhydride as detailed under Example I. Obtained 21.1 grams, B. P. 150-155 C./0.3 mm., n =1.5130.

Carbon, Hydrogen, Nitrogen,

Percent Percent Percent Calculated 61. 88 7. 99 11. 10 Found 51. 97 7. 84 11. 32

N-DIALKYLAMINOALKYL-B-AZABICYCLO (3:210) HEPTANE 2,4-DIONES Analysts, Percent 13. P., N-substltutent 0. Mm Carbon Hydrogen Nltrogen Calcd. Found Oalcd. Found Calcd. Found diethylamlnobutyl. 104-108 0. 2 66. 63 66. 71 9. 59 0. 55 11.10 9. 98 dlethylarnlnoamyL. -114 0.1 67. 63 67. 55 9. 84 0. 72 10. 52 10. 64 dletbylarnlnohexyL -124 0. 1 6B. 53 68. 44 10. 06 10. 11 9. 99 10. 09 dlbutylamlnoethyl. 109-115 0. 2 6B. 53 6B. 38 11). [)6 9. 98 9. 99 10. 15 dihexylaminoethyl. -129 0. 1 71. 38 71. 31 10. 78 10. 67 8. 33 8. 5D morphollnoethyl 142-148 0. 2 60. 48 60. 62 7.61 7.68 11. TI} 11. B1 plperldlnoetbyl 138-144 0. 2 66. 07 65. 98 8. 53 8. 55 1 l. 86 11. 90

propylamine with 0.2 mole of the anhydride as detailed under Example I yielded 31 grams of the title imide, B. P. 87-97" C./0.2 mm., n =1.4942.

Carbon, Hydrogen, Nitrogen,

Percent Percent Percent Calculated 62. 83 8. 63 13. 32 Found 62. 75 B. 71 13. 22

EXAMPLE IV N-diethylaminopropyl-3-azabicyclo(3:2:0 heptane- 2,4-dz'0ne simple and quaternary salts The imide.--Reaction of 0.1 mole of diethylaminopro- The m0nohydrochl0ride.-This was formed from the imide in isopropanol with excess alcoholic-HG! and was a white crystalline material, M. P. 182-3 C. Recrystallized from isopropanol-ethyl ether, M. P. 185-186 C.

Ionic chloride: Calculated-12.28%; found-12.31%.

The monomethi0dide.-This was formed from the imide in acetone with a slight excess of methyl iodide, and was a white crystalline material, M. P. 236-238 C. decomposition. Recrystallized from isopropanol, M. P. 239.5241 C. decomposition.

Ionic iodide: Calculated-32.l9%; found-32.12%.

From the foregoing description of a novel class of compounds, details of preparation and characterization of exemplary members of the class, it will be understood that, on the basis of the discovery and knowledge dis closed herein, other specific compounds can be made and variations in the methods of synthesis resorted to. The appended table contains additional examples of imides prepared by the procedures detailed herein. Therefore, the specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than the foregoing descriptive detailed examples, and all specific compounds and variations and methods which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

What is claimed and desired to be secured by United States Letters Patent is:

I. As a novel composition of matter, a compound selected from the group consisting of (1) compounds having the formula BIC-OH- where, in said formula, n is a number from 1 to 6, and R is selected from the group consisting of two alkyl groups with each alkyl group having from 1 to 6 carbon atoms and radicals which form, together with the nitrogen atom to which they are attached, a heterocyclic group selected from the group consisting of morpholino, piperidine and pyrrolidino, and (2) the acid addition salts and mono-quaternary salts of (l).

2. As a novel composition of matter, a mono-methonium salt of N-dimethylaminoethyl-3-azabicyclo(3:2:0)- heptane-2,4-dione.

3. As a novel composition of matter, a mono-metho- 6 nium salt of N-dimethylaminoethyl-3-azabicyclo(3:2:0)- heptane-2,4-dione.

4. As a novel composition of matter, a mono-methonium salt of N-dimethylaminopropyl-3-azabicyclo(3 :2:0)- heptane-2,4-dione.

5. As a novel composition of matter, a mono-methonium salt of N-diethylaminopropyl-3-azabicyclo(32:0)- heptane-2,4-dione.

6. As a novel composition of matter, a mono-methoniutn salt of N-morpholinopropyl-3-azabicyclo(3:2:0)- heptane-2,4-dione.

7. As a novel composition of matter, N-dimethylaminoethyl-3-azabicyclo( 3 :2 :0 heptane-2,4-dione.

8. As a novel composition of matter, the mono-methonium chloride of N-dimethylaminoethyl-3-azabicyclo- (3 :2:0)hpetane-2,4-dione.

9. As a novel composition of matter, N-diethylaminoethyl-3-azabicyclo(3 :2 0 heptane-2,4-dione.

10. As a novel composition of matter, the mono-methonium chloride of N diethylaminoethyl 3 azabicyclo- (3 :2 0)heptane-2,4-dione.

11. As a novel composition of matter, the mono-methonium chloride of N-dimethylamino-propyl-3-azabicyclo- (3 :2 0) heptane-2,4-dione.

References Cited in the file of this patent FOREIGN PATENTS 173,063 Great Britain Dec. 21, 1921 

1. AS A NOVEL COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS HAVING THE FORMULA 